Anti-cancer agents have various types such as an alkylating agent, a platinum agent, an antimetabolite, an antitumor antibiotic, and an antitumor plant alkaloid. These anti-cancer agents are effective for some cancers but not effective for other cancers. Even when an anti-cancer agent is confirmed to be effective for a certain cancer, the anti-cancer agent is effective for some patients and not effective for other patients, leading to interindividual differences. Whether or not a cancer of a specific patient has response to an anti-cancer agent is designated as sensitivity to the anti-cancer agent.
Irinotecan hydrochloride (CPT-11) is an anti-cancer agent which has been developed in Japan and which has a mechanism of antitumor action based on the inhibition of topoisomerase I. In Japan, CPT-11 indicated for non-small-cell lung cancer, small cell lung cancer, cervical cancer, and ovarian cancer was approved as an effective drug in January, 1994. Further, CPT-11 indicated for gastric cancer, colorectal cancer, breast cancer, squamous cell carcinoma, and malignant lymphoma was approved in July, 1995. Currently, CPT-11 in multi-drug therapy has been recognized to be one of standard chemotherapy, in particular, as a first-line or a second-line for colorectal cancer all over the world, and CPT-11 had been established the efficacy (Non-Patent Documents 1 to 6).
Meanwhile, clinical performance (including survival rate) attained by chemotherapy for advanced or metastatic colorectal cancer has been drastically improved through a combination therapy employing a key drug such as CPT-11 or oxaliplatin, which launched in 1990s, and a fluoro-pyrimidine drug such as fluorouracil (5-FU), which had been a main drug for the colorectal cancer therapy. However, the response rate of such chemotherapy is as low as about 50%. That is, the chemotherapy is not effective for half of the patients to whom an anti-cancer agent has been administered, concomitant with risky severe adverse events. Thus, there is urgent demand for establishing a marker for predicting the sensitivity to an anti-cancer agent, which marker enables determination of interindividual therapeutic response (i.e., responder/non-responder).
Generally, the therapy schedule of cancer chemotherapy requires a long period of time. After repetition of several courses of chemotherapy while emergence of adverse events is carefully checked, attainment of a therapeutic effect and continuation of the therapy are assessed. The assessment requires a long period of time and high medical cost, and an adverse event has actually been observed to a certain degree. Thus, if there were means for predicting whether or not individual patients can receive the effect of chemotherapy before or in an early stage of the therapy, the burden on patients and emergence of adverse events can be reduced or mitigated, leading to reduction in medical cost.
Although CPT-11 itself has anti-tumor activity, CPT-11 is activated by carboxyl esterase in the body, to thereby be converted into 7-ethyl-10-hydroxycamptothecin (SN-38), which has an anti-tumor activity about 100 times to some thousand times that of CPT-11. Co-presence of CPT-11 and SN-38 is thought to provide an anti-tumor effect. In hepatocytes, SN-38 is glucuronidated by UDP-glucuronosyltransferase (UGT), to thereby form SN-38 glucuronate conjugate (SN-38G) having no cytotoxicity. SN-38G is excreted mainly to bile and then transferred to the intestinal tract, and finally excreted to feces. A portion of SN-38G excreted to the intestinal tract is deconjugated by β-glucuronidase of enteric bacteria, to thereby form active SN-38 again. The thus-formed free SN-38 is metabolized and excreted via the steps of re-absorption by the mediation of a transporter present at the intestinal tract epithelium, enterohepatic circulation, glucuronate conjugation by UGT in intestinal epithelial cells, and the like (Non-Patent Document 7). In the course of this metabolism, SN-38 damages the intestinal mucosa, to thereby possibly induce diarrhea. Also, some studies revealed that SN-38 adversely affects bone marrow, where cell division actively occurs, to thereby induce erythrocytopenia, leukocytopenia, and thrombocytopenia.
One cause for adverse events such as severe diarrhea and neutropenia was confirmed to be a change in exposure amount of SN-38 in the body caused by genetic polymorphism of UGT1A1. However, regarding therapeutic effects, there has not been reported that the therapeutic effect can be predicted by pharmacokinetics, due to the complex disposition, which include conversion of CPT-11 (pro-drug) to SN-38 (active metabolite) and its detoxication; re-generation of SN-38 in the course of enterohepatic circulation; and metabolism of CPT-11 and formation of SN-38 from the metabolite thereof, and due to antitumor effect generally determined by the tumor-related factors. Meanwhile, it has been reported that the carboxyl esterase mRNA expression amount in peripheral mononuclear cells correlates with the AUC ratio of SN-38 to SN-38G but does not correlate with the tumor reduction effect (Non-Patent Document 8).
There have also been reported the following tumor-related factors relating to the sensitivity or resistance to CPT-11: mutation of topoisomerase I, which is a target of SN-38, and expression amount thereof; activity of carboxyl esterase, the enzyme being involved in transformation of CPT-11 to SN-38 (Non-Patent Document 9); and transporters (multidrug resistance protein (MRP)-1, MRP-2, and breast cancer resistant protein (BCRP)/ABCG2), which affect the intracellular accumulation of CPT-11 and SN-38. Studies have also been conducted on correlations of cell proliferation antigen Ki-67, tumor suppressor gene p53, etc. with response to CPT-11 therapy. Quite recently, in vitro, studies have been conducted to predict sensitivity to an anticancer agent systematically through combination of anti-cancer agent sensitivity data with microarray analysis data, and for camptothecin derivatives, topotecan has been studied (Non-Patent Document 10). Also, a clinical study have revealed that the plasma TIMP-1 level, TIMP-1 being a tissue inhibitor of metalloproteinase-1 having anti-apoptosis action, is significantly correlated with the clinical prognosis of a metastatic colorectal cancer patient having undergone CPT-11 +5-FU combination therapy (Non-Patent Document 11). As described above, many studies have been conducted on sensitivity (to CPT-11) predicting bio-markers due to their necessity. However, a study has revealed that neither topoisomerase I (target) nor thymidylate synthase (possible 5-FU-sensitivity predictive factor) has clear correlation with therapeutic response in 5-FU+CPT-11 combination therapy (Non-Patent Document 12). Therefore, no definite bio-marker capable of predicting therapeutic response has been established.